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Computational model of  the mouse heart

Multi-Scale Modeling of the Mouse Heart: From Genotype to Phenotype

Contents

• Contact Information
• Funding Agency 
• Research Emphasis 
• Disease Focus 
• Scales Examined 
• Biomedical, Biological &  Behavioral Areas
• Modeling Methods & Tools  
• Software Development 

Contact Information

Principal Investigator/Contact
Andrew McCulloch
University of California, San Diego
Phone: (858) 534-2547
Fax: (858) 534-6896
E-Mail: amcculloch@ucsd.edu
Project Website: http://cmrg.ucsd.edu and http://www.continuity.ucsd.edu

Co-PIs and Collaborators
Thomas K. Borg 
University of South Carolina School of Medicine

Robert L. Price
University of South Carolina School of Medicine

Grant Number - 506252

Funding Agency

National Science Foundation (NSF)

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Research Emphasis

The project proposes to develop new multi-scale computational models of the mouse heart that integrate functionally and structurally across multiple scales of biological organization from molecular networks to organ system.

The proposed new models will extend the scales of spatio-temporal integration now possible by up to three orders of magnitude. This proposed research will involve an important new collaboration between UCSD and investigators at the University of South Carolina, where researchers will perform very large-scale three-dimensional acquisitions and reconstructions of whole mouse hearts at sub-micron resolution using confocal microscopy. From these new data in normal and transgenic mice, the researchers will reconstruct highly detailed 3-D models of cardiac muscle fiber and sheet microarchitecture and cell connectivity via gap junctions. This will be used to construct three dimensional models with heterogeneous electromechanical properties.

The fully integrated computational models will be used to predict the effects of specific molecular alterations in G-protein coupled receptor signaling pathways on whole ventricular electromechanical function in the mouse heart. These predictions will be validated against measurements in transgenic mice over-expressing adenylyl cyclase type VI or Gαq, using magnetic resonance imaging and voltage-sensitive dye imaging.

G-protein coupled receptors (GPCRs) are a large super-family of cell-surface proteins whose function is to transduce information from extracellular space to the cell interior by stimulating (or inhibiting) second messenger systems.

Confocal laser scanning microscopy (CLSM or LSCM) is a valuable tool for obtaining high resolution images and 3-D reconstructions. The key feature of confocal microscopy is its ability to produce blur-free images of thick specimens at various depths. Images are taken point-by-point and reconstructed with a computer, rather than projected through an eyepiece.

Genotype is the genetic constitution (the genome) of a cell, an individual or an organism. The genotype of a person is her or his genetic makeup. It can pertain to all genes or to a specific gene. By contrast, the phenotype results from the interaction between the genotype and the environment. It is the composite of the characteristics shown by the cell, individual or organism under a particular set of environmental conditions.

Disease Focus

Cardiovascular Disorders 

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Scales Examined 

Time Scales

• Microsecond (μs)
• Millisecond (ms)
• Second(s)
• Minutes
• Hours
• Days
• Months

Biological Scales

• Molecular
• Molecular Complexes
• Sub-Cellular
• Cellular
• Multi-Cellular Systems
• Tissue
• Organ
• Organ Systems

Length Scales 

• Nanometer (nm)
• Micrometer (μm)
• Millimeter (mm)
• Centimeter (cm)

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Biomedical, Biological and Behavioral (BBB) Areas and Percent Focus

Genetically engineered mice (10%); cardiac anatomy and structure (10%); cardiac physiology (10%); cardiac myocyte biophysics (10%); signal transduction (10%) 

Modeling Methods and Tools (MMT)Areas and Percent Focus

Regulatory network systems models (12.5%); cell biophysical models (10%); tissue continuum constitutive models (10%); whole organ finite element models (12.5%); circulatory systems dynamics models (5%)    

Software Development